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Small molecule inhibitory leads against influenza RdRp

小分子抑制流感 RdRp

基本信息

批准号：
9119771
负责人：
Thomas Roy Webb
金额：
$ 55.9万
依托单位：
SRI INTERNATIONAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9119771
关键词：
Animal Model Binding Biochemistry Biological Assay Biology Cells Cessation of life Chemicals Chemistry Clinical Clinical Distribution Clinical Trials Communicable Diseases Department chair Development Disease Outbreaks Drug Kinetics Drug resistance Enzyme Inhibition Enzymes Evaluation Faculty G-Protein-Coupled Receptors Genome Goals Growth HIV Integrase Hospitalization Human In Vitro Infection Influenza Influenza A Virus, H1N1 Subtype Influenza Therapeutic International Label Lead Libraries Liver Microsomes Marketing Metabolism Metal Binding Site Molecular New Agents Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Point Mutation Polymerase Population Production Property Prophylactic treatment Proteins Publishing RNA Processing RNA-Directed RNA Polymerase Reagent Recombinants Replicon Reporting Research Research Personnel Resistance Safety Saint Jude Children&apos s Research Hospital Site Solubility Structure Terrorism Therapeutic Therapeutic Agents Time Toxic effect Treatment Efficacy United States Validation Viral Virion Virulent Virus Diseases Virus Replication Work absorption acute toxicity analog base biodefense design drug development drug discovery endonuclease flu activity improved in vitro Assay in vivo influenza epidemic influenza virus strain influenzavirus inhibitor/antagonist innovation insight killings lead series meetings mutant new therapeutic target novel novel therapeutics pandemic disease pandemic influenza pharmacophore product development protective efficacy receptor resistant strain respiratory scaffold screening seasonal influenza small molecule structural biology zanamivir

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a safe and effective new therapeutic agent for influenza virus infections that works by blocking influenza polymerase, which is a unique influenza protein that is critical for virus replication an infection. This project builds on the discovery of new active molecules found by the screening of targeted libraries with innovative influenza polymerase assays. The active molecules that were initially discovered were further developed into new drug-like molecules that are about 100 times more potent in the inhibition of influenza polymerase. The research plan proposes to further develop these compounds into optimized drug leads through additional cycles of library synthesis and directed medicinal chemistry. These lead compounds can then be transferred to GlaxoSmithKline (GSK), who is the product development partner as part of a "Partnership for Biodefense". GSK will be responsible for development, clinical trials and distribution of the new first-in-class influenza drug. Some of the major innovations that are associated with this work are; 1) Our original observation regarding the mechanistic similarity between the two-metal binding site of HIV integrase (which is a clinically validated target) and influenza endonuclease, this led to our novel hypothesis that the pharmacophore of these two mechanistically similar sites should share useful common features for targeted library design. 2) The novel specific design and associated development of the high throughput chemistry that allowed for the synthesis of a library of 5,992 new compounds that target the two-metal binding site pharmacophore. 3) Our extension of the internally developed IRdRp mini-genome (replicon) assay that allows for the targeted screening of >10,000 compounds. 4) The design and development of a completely novel in vitro fluorescent polarization (FP) binding assay using a fluorescently labeled known inhibitor of endonuclease and a recombinant PAn endonuclease subunit as the key reagents. 5) Our discovery of novel drug-like compounds that show good cell-based inhibition in the IRdRp replicon assay and also binding in the FP endonuclease assay. 6) Our demonstration that binding in the above FP assay correlates with the published enzyme inhibition for a set of known inhibitors of native influenza endonuclease. 7) The development of a new recombinant PAn construct that has given the first co-crystal structure of an inhibitor with PAn. The Specific Aims of this project are: Aim 1. Lead optimization of novel endonuclease, polymerase and dual inhibitors, using iterative library synthesis and directed medicinal chemistry to select two or more optimized leads for development. Aim 2. Evaluation of the protective and therapeutic efficacy of lead compounds in vitro and in vivo. Aim 3. Conduct lead optimization through non-GLP toxicity and pharmacokinetic studies for the most promising orally-active optimized lead candidates that meet the established criteria.

描述（由申请人提供）：本项目的总体目标是开发一种安全有效的新型流感病毒感染治疗药物，该药物通过阻断流感聚合酶发挥作用，流感聚合酶是一种独特的流感蛋白，对病毒复制和感染至关重要。该项目建立在通过创新的流感聚合酶检测筛选靶向文库发现新的活性分子的基础上。最初发现的活性分子被进一步开发成新的药物样分子，其抑制流感聚合酶的效力约为100倍。该研究计划建议通过库合成和定向药物化学的额外循环将这些化合物进一步开发为优化的药物先导物。这些先导化合物然后可以转移到葛兰素史克（GSK），谁是产品开发合作伙伴的一部分，“生物防御合作伙伴关系”。葛兰素史克将负责这种新型一流流感药物的开发、临床试验和分销。与这项工作相关的一些主要创新是：1）我们最初观察到HIV整合酶（其是临床验证的靶标）和流感核酸内切酶的双金属结合位点之间的机制相似性，这导致我们的新假设，即这两个机制相似位点的药效团应该共享用于靶向文库设计的有用的共同特征。2)新的特定设计和高通量化学的相关开发，允许合成5，992种靶向双金属结合位点药效团的新化合物库。3)我们扩展了内部开发的IRdRp微型基因组（复制子）检测，允许对> 10，000种化合物进行靶向筛选。4)设计和开发了一种全新的体外荧光偏振（FP）结合试验，使用荧光标记的已知核酸内切酶抑制剂和重组PAn核酸内切酶亚基作为关键试剂。5)我们发现了新的药物样化合物，其在IRdRp复制子测定中显示出良好的基于细胞的抑制，并且在FP内切核酸酶测定中也显示出结合。6)我们证明了上述FP测定中的结合与公开的天然流感核酸内切酶的一组已知抑制剂的酶抑制相关。7)开发了一种新的重组PAn构建体，该构建体首次给出了抑制剂与PAn的共晶体结构。该项目的具体目标是：目标1。使用迭代文库合成和定向药物化学来优化新型核酸内切酶、聚合酶和双重抑制剂，以选择两种或更多种优化的先导物用于开发。目标二。评价先导化合物在体外和体内的保护和治疗功效。目标3.通过非GLP毒性和药代动力学研究对符合既定标准的最有希望的口服活性优化候选药物进行药物优化。